Hydrochloric Acid → Methyl 4-(4-(7-(6-cyano-5-(trifluoromethyl)-pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoate

HRID 515814Notes

Reaction equation

HRID 515814 reaction equation
[N:1]([C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)=[C:2]=[S:3].C([C:18]1([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19]1)#N.[CH3:35][OH:36].Cl.[CH3:38]N(C=O)C>O>[C:10]([C:7]1[N:8]=[CH:9][C:4]([N:1]2[C:35](=[O:36])[C:18]3([CH2:21][CH2:20][CH2:19]3)[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:38])=[O:33])=[CH:25][CH:24]=3)[C:2]2=[S:3])=[CH:5][C:6]=1[C:12]([F:15])([F:13])[F:14])#[N:11]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 887MethanolHCID 6228DimethylformamideHCID 250199805-Isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile2×HCID 667220494-(4-(1-Cyanocyclobutylamino)phenyl)butanoic acid2×

Product 1

HCID 86683474Methyl 4-(4-(7-(6-cyano-5-(trifluoromethyl)-pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of 5-isothiocyanato-3-trifluoromethylpyridine-2-carbonitrile (Intermediate 10, 582 mg, 2.54 mmol) and 4-(4-(1-cyanocyclobutylamino)phenyl)butanoic acid (Intermediate 80, 410 mg, 1.59 mmol) in DMF (3 mL) was stirred at room temperature overnight. To this mixture were added methanol (4 mL) and HCl (2M, 2 mL) and the resulting mixture was refluxed for 3 h. After being cooled room temperature, the reaction mixture was poured into cold water and extracted with EtOAc (3×). The organic layers were dried over magnesium sulfate and concentrated to dryness. Column chromatography of the residue on silica gel (Hexane:EtOAc=4:1) afforded 256 mg of methyl 4-(4-(7-(6-cyano-5-(trifluoromethyl)-pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoate as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (d, 1H), 8.38 (d, 1H), 7.42 (d, 2H), 7.36-7.19 (m, 2H), 3.70 (s, 3H), 2.87-2.75 (m, 2H), 2.75-2.53 (m, 4H), 2.42 (t, 2H), 2.26 (m, 1H), 2.05 (m, 2H), 1.78-1.61 (m, 1H). LCMS [M+1]+ 503.0.

Workup

  1. temperaturethe resulting mixture was refluxed for 3 h
  2. temperatureAfter being cooled room temperature
  3. extractionextracted with EtOAc (3×)
  4. dry with materialThe organic layers were dried over magnesium sulfate
  5. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-748ffc42b9b14e29bb9e3a9667b99d1b
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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